Sweetener derivatives

ABSTRACT

Dihydrochalcones of the formula ##SPC1## 
     Wherein D is a derivatizing group, Y is a polar group, X is hydrogen or hydroxyl and R is a lower alkyl, their preparation and their use as non-sugar sweeteners are disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compositions for imparting sweetness to ediblecompositions such as foodstuffs.

2. Reference to Related Application

This application is related to United States Patent Application SerialNumber 477,744, filed of even date by the present inventors andconcerning nonderivatized forms of some of the present dihydrochalcones.

THE PRIOR ART

Dihydrochalcones are compounds having a ##SPC2##

Basic structure. A range of dihydrochalcone materials, both natural andsynthetic, has been disclosed in the prior art. These materials varyfrom one another by the nature and placement of substituents on thearomatic rings.

A limited number of the dihydrochalcones, such as those disclosed inHorowitz and Gentili's U.S. Pat. Nos. 3,087,871 (issued Apr. 30, 1963)and 3,583,984 (issued June 8, 1971), and Farkus et al's Hungarian PatentApplication, CI-1196, have taken on special interest because they aresweet. They appear to be nontoxic and potentially attractive as nonsugarsweeteners -- offering the advantages of being essentially noncaloric,not having an insulin requirement, and sometimes being relatively"sugar-like" in taste.

As pointed out in the cited Horowitz and Gentili patents and theirchapter in the Book Sweeteners and Sweetness; Birch, Green, and Coulson,Eds, Applied Science Publishers, Ltd., London, pp. 69-77 (1971), thedihydrochalcones' sweetness depends upon the nature of the aromatic ringsubstituents and their exact location on the rings. A change which isrelatively minor from a chemical structure point of view will very oftenhave a major effect on the taste properties of the dihydrochalconeproduct. No broadly applicable rules have been developed to show orpredict whether new dihydrochalcones will be sweet or not. This extremesensitivity of taste and structure makes the formation of derivatives ofdihydrochalcones very difficult when a retention of sweetness isdesired. This means that as a rule under prior art teachings, it isreally not possible to vary by derivatization the molecular size orproperties, such as its polarity or solubility, of a dihydrochalconewithout jeopardizing the sweetness properties of the material. As it isoften of interest to make minor variations in a sweet molecule'snonflavor properties to enhance its usefulness as a sweetener, thisinability is a real problem.

STATEMENT OF THE INVENTION

While studying a group of sweet dihydrochalcones, themselves believed tobe new compounds, a point at which derivatization may be effectedwithout destroying the compound's sweetness has been discovered. Moreparticularly, it has been found that sweet dihydrochalcones representedby General Formula (I): ##SPC3##

wherein Y is a polar group, X is hydrogen or hydroxyl, and R is a lowersaturated alkyl, can be derivatized at the methylene link intermediatepolar group Y and the oxy bridge of their 4 substituent. This positionis indicated in General Formula (I) by an arrow. Derivatization takesplace by replacing one of said methylene link's hydrogens with aderivatizing group, D. When sweet dihydrochalcones are derivatized inaccord with this invention, they retain their sweetness. The derivatizeddihydrochalcones are represented by General Formula (II), ##SPC4##

wherein Y, X and R are as already defined, and D is a derivatizinggroup.

DETAILED DESCRIPTION OF THE INVENTION The Dihydrochalcones

The dihydrochalcones which are derivatized in accordance with thisinvention have the set chemical structure shown in General Formula (I).In their derivatized form, they have the structure shown in GeneralFormula (II). As shown in these formulae, they contain a lower saturatedalkoxy group at their 4' position. This alkoxy group is selected fromamong methoxy, ethoxy, propoxy, and butoxy groups (including the variouspropoxy and butoxy isomers). Preferably the 4' position carries amethoxy or isopropoxy, with methoxy being the most preferred 4'substituent. At the 4 position they contain a methoxy group, to which isattached a polar group Y. Polar group Y may include, for example, acarboxylic acid group (--COOH); a carboxylic acid salt (--COOM, whereinM is a pharmacologically acceptable cation such as the pharmacologicallyacceptable alkali metal, alkaline earth, ammonium and transition metalcations, especially sodium and potassium cations); a hydroxyl group(--OH); a primary amide group (--CONH₂); a sulfonic acid group (--SOH₃)or a sulfonic acid salt (SO₃ M, wherein M is as defined above). Amongthe polar groups the carboxylic and sulfonic acids and theircorresponding --COOM and --SO₃ M salts are preferred, with thecarboxylic acid and its sodium salt comprising most preferred polargroups.

DERIVATIZATION AND DERIVATIZING GROUPS

A derivatizing group, D, is present as a substituent on the 4 positionmethoxy group. D groups must be organic, containing at least one carbonatom. Suitable derivatizing groups include any group which, whencovalently attached to the dihydrochalcone, brings about a useful changein its properties, such as its solubility in aqueous media, its abilityto crystallize, its diffusivity or permeability through membranes, orits sweet flavor characteristics. When it is desired to increase thedihydrochalcones' solubility in aqueous media, derivatizing group D isselected from hydrophilic organic groups, such as linear polyethers, forexample, the polyethoxyethers (CH₃ [-O-CH₂ -CH₂ ]_(n) -O) (wherein n isfrom about 1 to about 30) marketed by Union Carbide under the name"Carbowax" and polyethylene glycol; polyhydroxy materials, for example,polyhydroxy-substituted polymethylene chains as found in polyvinylalcohol; and polyhydroxy-substituted ethers, for example, polyglycidol.A preferred class of derivatizing groups D are saturated hydrocarbonsand oxyhydrocarbons having from 1 to 6 carbons and 0 to 3 oxygens. Theseinclude lower alkyls such as methyl, ethyl, butyl, cyclohexane and thelike; alkoxy groups such as methoxy, ethoxy and isobutoxy; and lowerpolyethoxy ethers.

In a special application, derivatizing group D is a group whichincreases the molecular bulk or size of the dihydrochalcone molecule toan extent that the molecule is too large to pass through the walls ofthe gastrointestinal tract and thus is not absorbable into the body wheningested. While to date no severe toxicological problems have beenassociated with the dihydrochalcones, rendering them nonabsorbable bythis derivatization would eliminate any queston of danger. As a generalrule, a group D should have a molecular weight of at least about 700 torender a dihydrochalcone molecule too large to be absorbable. Preferablyin this application, D has a molecular weight of from 100 to 10,000,although larger materials can be used, if desired.

In another embodiment of this invention, group D serves as a bridge orlink between two or more dihydrochalcones of the type described herein.Such a product is represented by Formula (III), ##SPC5##

wherein Y, n, D, and R are as defined in Formula (II) and n is aninteger greater than 1, preferably from 2 to 20, and more preferablyfrom 2 to 15. With such a material, the plurality of dihydrochalconegroups itself contributes to a large molecular size and can render themolecule large enough to not be absorbed through the walls of thegastrointestinal tract, if such property is sought.

The derivatizing group, D, is covalently bonded to the dihydrochalcone.In its attachment to the dihydrochalcones, the D group displaces one ofthe hydrogens on the dihydrochalcone's 4-position methoxy group.

PREPARATION

The derivatized dihydrochalcones of this invention may be produced byalkylating a flavanone such as hesperetin with a polar group andderivatizing group-containing agent and thereafter opening and reducingthe alkylation product to the desired dihydrochalcone. This preparationis illustrated as follows: ##SPC6##

wherein D, Y and R are as hereinabove set forth and L is a leaving groupsuch as chloride, tosylate, iodide, bromide, methylate, or the like.

The alkylation reaction is best carried out in a reaction solvent inertto the reactants and conditions employed, such as dimethylformamide,tetrahydrofuran, glyme, acetone, or hexamethylphosphoramide. Thisreaction is often carried out in the presence of an added leaving groupscavenger which reacts with liberated leaving groups and prevents theirbuildup in the reaction mixture. As an example, when Br⁻ is the leavinggroup, a weak inorganic base such as K₂ CO₃, Na₂ CO₃, or K₃ PO₄ may beadded to form KBr or NaBr, which precipitates from the reaction mixture,avoiding buildup. This reaction may be carried out at mild conditionssuch as at temperatures of from about room temperature (20°C) up toabout 100°C.

The opening and hydrogenation reaction is carried out by a strong baseand hydrogenation conditions. Any strong base, for example, sodiumhydroxide, lithium hydroxide, or tetramethyl ammonium hydroxide may beused. The hydrogenation may be carried out catalytically as shown, inthe presence of a suitable transition metal or precious metal catalyst(such as nickel, cobalt, platinum or palladium catalysts) and molecularhydrogen at pressures from atmospheric up to as much as about 100 psigand temperatures of from about room temperature (20°C) up to about125°C; or it may be effected by reaction with a hydrogen-carrying agentsuch as diimide.

USE OF THE DIHYDROCHALCONES

These derivatized dihydrochalcones find application as sweeteners. Inthis case they are admixed with edible substances such as food,beverages, medicines, and the like, in amounts effective for imparting adesired degree of sweetness. The amount of dihydrochalcone employed canvary widely, just as the amount of natural sugar sweetener varies fromperson to person and food application to food application. As a generalrule, the weight of derivatized dihydrochalcone added will be about1/100 - 1/500 the weight or sucrose required to yield the samesweetness. Thus, additions of from say 0.0001% up to about 0.05% byweight (basis edible substance) may usefully be employed.

The derivatized dihydrochalcones are added to the edible composition bymixing methods known in the art. They may be added as solids or assolutions. They may be used alone or as the primary sweetener in acomposition, or they may be one of several sweeteners in the finalcomposition; sucrose, or another natural sweetener, or another syntheticsweetener also being added.

These dihydrochalcones, their preparation and their use are furtherdiescribed in the following Examples. These are to illustrate theinvention and are not to be construed as limitations on this invention,which is instead defined by the appended claims.

EXAMPLE I

This example describes the preparation of a derivatized dihydrochalconein accordance with the present invention. In part A, an alkylating agentis prepared; in part B, alkylation is effected; and in part C, openingand reduction are set forth.

A. into a 1,000 ml three-neck flask is charged 288.5 g oftriphenylphosphine, and 96.0 g of 2-(2-methoxyethoxy) ethanol (CH₃--O--C₂ H₄ --O--C₂ H₄ --OH). The mixture is stirred and 178 g ofN-bromosuccinimide is added over 11/2 - 2 hours. The mixture warms andis stirred for 1/2 hour. It is then heated and a vacuum is pulledcausing 138.5 g of an oil to distill overhead. This is collected andanalyzed and found to be principally 2-(2-methoxyethoxy) ethyl bromide.Redistillation yields this bromide in a pure form.

Next, 300 ml of methanol, 2.3 g of metallic sodium and 13.6 g ofdimethyl malonate are combined; 18.3 g of the 2-(2-methoxyethoxy) ethylbromide is added; and the mixture is refluxed overnight. Methanol isremoved by vacuum evaporation, and a diester product, CH₃ --O--C₂ H₄--O--C₂ H₄ --CH(CO₂ CH₃)₂, is recovered by vacuum distillation.

1.17 Grams of this ester is added to 1.12 g of potassium hydroxide in 12ml of 1:1 methanol-water, and stirred for 1/2 hour. Methanol is removedand concentrated hydrochloric acid as added to pH 1. The mixture isextracted into ethyl acetate. The extract phase is dried and stripped ofethyl acetate to yield off-white crystals of the diacid

    CH.sub.3 --O--C.sub.2 H.sub.4 --O--C.sub.2 H.sub.4 --CH(CO.sub.2 H).sub.2.

0.94 Grams of this diacid is dissolved in diethyl ether. 0.732 Grams ofbromine is added and the mixture is stirred and heated for about onehour. The mixture is washed with brine to remove HBr and dried overMgSO₄. Ether is removed, yielding crystals of the bromodiacid,

    CH.sub.3 --O--C.sub.2 H.sub.4 --O--C.sub.2 H.sub.4 --CBr (CO.sub.2 H).sub.2,

which are heated at 130°-140°C for 1 hour to yield the bromomonoacid,##STR1## which is isolated by vacuum distillation. This preparation isrepeated on a larger scale to yield 3.3 g of the bromomonoacid, which isdissolved in 50 ml of dichloromethane. To this solution are added 5.6 mlof methanol and 94 mg of p-toluenesulfonic acid hydrate catalyst; andthe mixture is refluxed overnight. The next day, the solvent is vacuumevaporated and the bromomonoester,

    CH.sub.3 --O--C.sub.2 H.sub.4 --CHBr--CO.sub.2 CH.sub.3,

is recovered.

B. 28 milligrams of anhydrous-potassium carbonate, 60 mg of hesperetin,and 0.4 ml of dimethylformamide (DMF) are combined and stirred at roomtemperature. 102 Milligrams of the bromomonoester of part A are addedalong with 0.4 ml of DMF. The mixture is stirred for 23 hours andanalyzed by thin layer chromatography and found to contain the flavanonealkylation product, ##SPC7##

which is recovered by extraction into ethyl acetate from water followedby drying and concentration and purification by preparative thin layerchromatography.

C. 58 milligrams of the flavanone alkylation product of part B isdissolved in 5.0 ml of 5% potassium hydroxide. To this is added 25 mg of5% Pd on charcoal, and the mixture is capped with an excess of hydrogen.The mixture stands at room temperature for 19 hours. It is filtered,acidified to pH 2 with 10 % hydrochloric acid, and extracted with ethylacetate. The extracts are dried and evaporated to yield a colorless oil,which is purified by preparatory scale thin layer chromatography toyield a product which is identified as the derivatized dihydrochalcone;##SPC8##

This material has a sweet taste. When prepared in larger amounts, it isadded to soft drinks, coffee, cough syrups, gelatin desserts and otheredible compositions in amounts of from about 0.0003% to 0.05% by weightto impart a sweet taste thereto.

EXAMPLE II

The experiment of parts B and C of Example I is repeated with one majorchange. As an alkylating agent is employed 2-bromoethylpropionate. Theresulting final product is the dihydrochalcone ##SPC9##

product is sweet, and when added to edible compositions alone or incombination with saccharin or sugar, imparts a sweet taste to the ediblecompositions.

EXAMPLE III

Carbowax 350, CH₃ O(CH₂ CH₂ O)_(n) -CH₂ CH₂ OH (where n ≅7), isconverted in the same manner as described in Example I, Part A, to thecorresponding bromo methyl ester derivative, ##STR2## This material isused to alkylate hesperetin by the same procedure (K₂ CO₃, DMF) asdescribed in Example I, Part B, and the resulting ester hydrogenated in5% aqueous KOH to the desired dihydrochalcone carboxylic acid, ##SPC10##

where n ≅7, utilizing the procedure of Example I, Part C.

EXAMPLE IV

Hesperetin (125 mg) is dissolved in 5 ml of dry tetrahydrofuran, cooledto ˜0°, and treated with one equivalent of sodium hydride (42.1 mg of57% dispersion). After stirring at room temperature for 3 hours under anargon atmosphere, the reaction mixture is evaporated to dryness underreduced pressure.

The resulting sodium salt of hesperetin is added to 1 ml of freshlydistilled glycidol and the mixture stirred at room temperature under anargon atmosphere for 30 hours. The unreacted monomer is removed byheating the reaction mixture at ˜0.5 mm and 140° as described by S.Sandler and F. Berg in J. Polymer.Sci., I, pp. 1253-1259 (1966).

The resulting crude reaction mixture is purified by chromatography onBio-Gel P-2 using 0.02 M phosphate buffer as the eluant.

After de-salting and freeze-drying of the desired fractions, theflavanone-polyether is converted to the desired dihydrochalcone##SPC11##

where n ≅5 by hydrogenation in aqueous 5% KOH as described in theprocedure of Example I, Part C.

We claim:
 1. A compound of the formula ##SPC12##wherein Y is acarboxylic acid or a pharmacologically acceptable salt thereof, D is alinear polyether of the formula CH₃ --(O--CH₂ --CH₂)_(n) -- wherein nhas a value of from 1 to 30 inclusive, and R is a lower alkyl of from 1to 4 carbon atoms inclusive.
 2. A compound of the formula##SPC13##wherein Y is a carboxylic acid or a pharmacologicallyacceptable slat thereof, D is a polyglycidol ether of the formula##EQU1## wherein n equals about 5, and R is a lower alkyl of from 1 to 4carbon atoms inclusive.
 3. The compound of claim 1 wherein n has a valueof from 1 to about 7 inclusive and R is methyl.
 4. The compound of claim3 wherein n has a value of 1 and Y is a --COOH group.
 5. The compound ofclaim 2 wherein R is methyl and Y is a --COOH group.